Viruses such as hepatitis B virus (HBV), hepatitis D virus (HDV), human immunodeficiency virus (HIV) are greatest threats to human health. For example, viral hepatitis B (hepatitis B) is caused by hepatitis B virus and mainly in the form of inflammatory lesions of the liver, leading to damage to multiple organs. World Health Organization (WTO) survey results show that there are 240 million cases infected with chronic hepatitis B and 780,000 cases died each year from hepatitis B, where 650,000 cases die from cirrhosis and liver cancer caused by chronic hepatitis B and 130,000 cases die from acute hepatitis B. Hepatitis B has been an critical and global issue for health.
Anti-HBV drugs generally include a class of nucleotide drugs such as adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), entecavir, lamivudine and telbivudine. These drugs act through activation into a triphosphate metabolite in cells to inhibit the DNA or RNA polymerase activity of the virus, thus preventing the synthesis of DNA or RNA and inhibiting viral replication.
Some nucleotide compounds, such as adefovir, tenofovir, etc., are highly electronegative at physiological pH and thus have poor transmembrane ability and low bioavailability for oral administration. Meanwhile, oral administration of such compounds may increase toxic effect to gastrointestinal tract and kidney. However, the nucleotide compounds can be esterified to form ester prodrugs such as adefovir dipivoxil and tenofovir disoproxil fumarate, improving the bioavailability and tissue distribution. However, before being taken up by hepatocytes, most of the ester prodrugs may be hydrolyzed to electronegative bioactive components (such as adefovir and tenofovir) by the ester hydrolase which is widely distributed in the body. Such components do not easily enter the hepatocytes, but are actively transported and absorbed by the renal proximal tubule causing nephrotoxicity.
Structure of the cyclophosphate (4-aryl-2-oxo-1,3,2-dioxaphosphorinane) precursor ensures excellent liver-specific delivery performance and its mechanism is very clear. As shown in FIG. 1, 4-aryl-substituted position is specifically catalyzed by CYP3A of cytochrome P450 isozyme family in hepatocytes to give a hydroxyl group followed by ring-opening to form an electronegative phosphate intermediate. This intermediate is maintained within the cell due to the difficulty in passing through the cell membrane. The electronegative phosphate intermediate is hydrolyzed and β-eliminated to form a nucleoside monophosphate compound under catalysis of phosphodiesterase. The nucleoside monophosphate compound is then catalyzed by nucleotide kinases to form a bioactive nucleotide triphosphate compound. At the same time, a metabolic by-product aryl vinyl ketone is removed by 1,4-addition reaction with glutathione, which is abundant in hepatocytes and has antioxidation and free radical-scavenging activity. In addition, the addition product has not been reported to have side effects.
Using adefovir as an active component, it is found that through modification of substituents on the aryl group, for example mono-substitution, disubstitution, a compound substituted with chloride at a meta-position on the aromatic ring, i.e., pradefovir, is metabolized to adefovir in the presence of CYP3A enzyme at a highest metabolism rate, nearly 5 times that of the compound substituted with chloride at 3- and 5-positions on the aromatic ring (US200707214668 B2).

However, there is still a lack of a viral inhibitory compounds with high activity, strong liver delivery specificity, and low toxic and side effects. Therefore, there is a need in the art to develop a novel antiviral compound with high activity, strong liver delivery specificity and low toxic and side effects.